Tumor-intrinsic CD74 expression mediates immune evasion in lung cancer with COPD

To better elucidate the complex interaction between COPD and NSCLC, we comprehensively characterized immune cell dynamics and transcriptome profiles of malignant cells in tumor tissues from NSCLC patients with COPD using single-cell RNA sequencing (scRNA-seq). We observed increased fractions of exhausted CD8+ T cells, CCL18+ tumor-associated macrophages (TAMs), and LAMP3+ dendritic cells (DCs) in the immune component of NSCLC with COPD compared with the findings in NSCLC without COPD. Remarkably, a critical cluster of malignant cells from NSCLC with COPD samples, characterized by high expression of CD74, significantly exhibited an epithelial-immune dual signature and was associated with poor prognosis. Interestingly, we found that CD74 facilitated phosphorylation of MAPK/STAT3 to mediate PD-L1 expression and further suppressed CD8+ T cell function, triggering LC progression. Our study provides a comprehensive profiling of the multi-cellular ecosystem of NSCLC with coexisting COPD and reveals that CD74+ cancer cells are potential targets for immunotherapy.